Allo pregnane compounds and process



United States Patent ALLO PREGNANE COMPOUNDS AND PROCESS Carl Djerassi, Birmingham, Mich., and George Rosenkranz, Mexico City, Mexico, assignors, by mesne assignments, to Syntex S.A., Mexico City, Mexico, a corporation of Mexico No Drawing. Original application Sept. 3, 1952, Ser. No. 307,722, now Patent No. 2,773,079, dated Dec. 4, 1956. and this application Oct. 3, 1956, Ser. No.

Claims priority, application Mexico Sept. 20, 1951 8 Claims. (Cl. 260-23955) The present invention relates to novel cyclopentanophenanthrene derivatives and to a method for the prepa ration thereof. More particularly, the present invention relates to certain novel intermediates useful for the preparation of allopregnane-17a,2l-diol-3,l1,20-trione (dihydroallocortisone) which can be readily converted to cortisone in accordance with our United States application, Serial Number 218,095, filed March 28, 1951, and to a novel process for the preparation thereof.

In our United States application, Serial Number 291,- 556, filed June 3, 1952, there is disclosed a method for the preparation of 3,8,11a-dihydroxy sapogenins from a for example, 22-isoallospirostan-3fl,llet-diol may be converted into the corresponding triacetate of A -furostene-3fl,1la,26-triol which on oxidation with chromic: anhydride under the conditions set forth in our United States application, Serial Number 287,821, filed May 14, 1952, can be degraded to A -allopregnene-3,8,1lat-diol diacetate.

It has been further discovered, in accordance with the present invention, that hydrogenation of the 16-17 dou-- ble bond of the last mentioned compound gives a corre sponding saturated allopregnane compound and that this compound may be readily converted as hereinafter set forth in to the corresponding allopregnane-3p,11a,17a-' triol-20-one.

It has further been discovered in accordance with the: present invention, that the last mentioned triol may be converted in to allopregnan 318,17 diol 11,20 dione which may readily be converted in to dihydroallocortisoneas has already been described in the application of Rosenkranz, Pataki and Djerassi, Serial Number 288,311, filed May 16, 1952. In the alternative, the allopregnantriolone can be brominated with one mol of bromine to give thecorresponding 21-bromo derivative which is thereafter converted in to the 21-monoacetate which may thereafter be oxidized with a mild oxidizing agent to form dihydroallocortisone.

The production of allopregnan-3j3,lla,17u-triol-20-one from 22-isoallospirostan-3p,1lwdiol may be illustrated by the following formula:

] AoO- Acetic Anhydride HO I 200 0. A00

Oxidation Chromic Anhydride and Mild Saponification CH3 (3H (3:0 3:0

AcO-

] AcO-- Hydrogenation A 1 A00 I lEnolization (EH1 CH5 ("J-0A C t, :0 011 AcO-f now t Oxidation and. Saponifleation A00 I HO I A -sapogenin such as A -22-isoallospirostene-3,6,1lot-diol- 7-one.

In accordance with the present invention we have discovered that compounds of the type just referred to, as

In the foregoing equation AC represents an acetoxy 0 group although it may be understood thattit may represent other lower fatty acid groups depending on the type of anhydride utilized in the reaction.

In practicing the reaction above outlined the sapogenin, -i.'e.,'22-isoallospirostan-*3fi;1lu-diol is dissolved in a suitable lower fatty acid anhydride such as acetic anhydride and heated in ,asealedtube at a temperature of approximatch 1 200 'C., for a relatively long period of time such 8 hours. Thereafter it is poured into water, purified and evaporated to dryness to give an oily residue. The oilyresidueof the step just referred to is then dissolved inalower {fatty acid such as acetic acid together-with an organic solvent such as ethylene dichloride and a small amount of water with heating until all of the oil is dissolved. The solution-is cooled to below room temperature' as for-example 1 -"C., anditreated slowly with stirring with a solution -of chromic anhydride in acetic acid togetherwitha small amount-ofwater. The mixture is allowed tostand for a-short period oftime as for example 2 hours and the ethylene .dichloride layer separated by .decantation. The aqueous layer is then extracted with a suitable solvent such as chloroform and the ethylene dichloride solution and chloroform solution is purified and combined. *A fter evaporation the residue is dissolved in a -rriixed solvent such as benzene and hexane "and chromatographed in an-alumina column. The alumina causes amild saponificationand the product is A -allopregnene=3y3, ll-a-diol one diacetate.

"The A compound is then-hydrogenated as by shaking withhydrogen-at room temperature and pressure together-with -a hydrogenation catalyst such as 10% palladium'on-barium sulphate. When the absorption of hydrogen ceased, i.e., in approximately 1 hour, the catalyst isfilteredoff; and the solntion evaporated to dryness. The residue on recrystallization gave allopregnane 3,8,1ladiol-ZO-one diacetate. From the diacetate of the previous step thecorresponding 17a-triol compound could then be prepared-by enolizing the al lopregnan-3fl,11a-diol-20-one diacetate'as with a lower fatty acid anhydride such as acetic anhydride in the presence of a catalyst such as ptoluenesulphonic acid followedtby oxidation with an aromatic per acid such as perbenzoic acid and saponification of the oxidation product undermild conditions, i.e., room temperature or below with methanolic alkali metalhydroxide such as sodium hydroxide. The resultant product, allopregnane-3,B,l1a,17 x-triol-20-one may then be treated with a mild oxidizing agent to form allopregnan- 3,11,20-trione-17a-ol which can be selectively hydrogenated as with Raney nickel catalyst in alcohol solution to This process form al1opregnan-3 3, 17 ot-diol-1 1,20-dione. is outlined in the following equations:

. lThe .mildaoxidizingr.agent-indicated above may be an .N,halo-acid;;.amide:preferably in pyridine such as N Bromination OHzBr -1-1no1e-Bromine 1 sodium Iodide folloWdB'y" Potassium Acetate QHzOA 2 12949 Mild Oxidizing HO- Agent In the .above equation AC represents the acetate radical, although other lower fatty acid esters may also be formed by the corresponding reagents.

In practicing the process steps above outlined the allopregnane-3 8i11a,l7a-triol-20-one is dissolved in a suitable solvent and monobrominated to give the corresponding 2l-bromo derivative which is in turn reacted with sodium iodide to give the corresponding 2l-iodo compound which may be transformed with potassium acetate into the 2l-monoacetate as above indicated. Thereafter the 2l-acetate is treated with a mild oxidizing agent of the type previously set forth, i.e., N-bromoacetamide or chromic anhydride under mild conditions.

The following examples serve to i.lustrate the present invention butare not intended to limit same:

Example I A -allofurostene-3}8,11a,26-triol triacetate. A solution of 5 g. of 22-isoallospirostan-3fi,1la-diol in 20 cc. of acetic" anhydride .washeated at 196 in a sealed tube during 8 hours and then poured in water. The mixture was extracted with ether and the ether solution "was Washed with water, sodium bicarbonate and water until neutral, dried over-sodium sulphate and evaporated to dryness. 4.6 g of an oily residue was obtained which was used -forthe next step without further purification.

Example II A -allopregnene-3fi,l1u-diol-20-one diacetate. 4.6 g. of A -allo furostene-3,B,1la,26-triol triacetate obtained according to Example. .l..were dissolved in a mixture of 45 cc. of aceticgacid, 36 cc. of ethylene dichloride and 15 cc. of water, heating until all dissolved. The solution was cooled to-15 and treated drop by drop and with mechanical stirring with a solution of 1.4 g. of chromic anhydridet in 2.2 cc. of water and 22 cc. of acetic acid. After 2 hours standing at room temperature the mixture was poured in water and the layer of ethyleneJdichloride was separated by -de'c an'tatioii."*-Tlie aque0us layer was extracted with chloroform and'lth'e combined chloroform and ethylene dichlo ride solution was washed several times with water, dried over sodium sulphate and evaporated to dryness. The residue was dissolved in a mixture of 50 cc. of benzene and 200 cc. of hexane and chromatographed in a column with 250 g. of alumina. The fractions eluted with benzene-ether (30:20 and 40:10) were combined and evaporated to dryness. The residue crystallized upon digestion with a mixture ether-pentane to yield 1.6 g. of A -allopregnene-3B,11a-diol-20-one diacetate having ultraviolet absorption maximum at 238 ,u (log 6 4.12).

Example Ill Allopregnane-3p,11a-diol-20-one diacetate. A solution of 600 mg. of A -a1lopregnene-3fi,11a-diol-20-one diacetate in 100 cc. of ethyl acetate was shaken at room temperature and atmospheric pressure under an atmosphere of hydrogen with 115 mg. of palladium on barium sulphate catalyst. The absorption of hydrogen ceased after one hour. The catalyst was filtered and the solution was evaporated to dryness and the residue was crystallized from hexane-acetone to give 510 mg. of allopregan-3B,lla-diol-20-one diacetate, which in contrast to the starting material, showed no selective absorption in the ultraviolet spectrum. Conventional saponification gave the free compound.

Example IV Allopregnan-3/3,11a,17a-triol-20-one. A solution of 2 g. of allopregnan-3;3,11a-diol-20-one diacetate and 1 g. of p-toluenesulphonic acid in 170 cc. of acetic anhydride was slowly concentrated to a volume of 20 cc. in the course of 5 hours and then it was poured in ice Water containing 3 cc. of pyridine. The product was extracted with ether, washed with 2% sodium hydroxide and water until neutral, dried over sodium sulphate and evaporated to dryness. The residue was dissolved in hexane and passed through a column of washed alumina in order to eliminate impurities. The solution was concentrated to dryness to leave 2.15 g. of A -allopregnene-3fi,11a,- 20-triol triacetate which was not crystallized but directly dissolved in 20 cc. of chloroform and let to react during 40 hours at room temperature with 13 cc. of a chloroform solution of perbenzoic acid containing 63 mg. of acid per cc. The mixture was diluted with more chloroform and washed with sodium iodide, sodium thiosulphate, sodium carbonate and water, and concentrated to a small volume. The solution was then treated during 30 minutes at room temperature with 1 g. of sodium hydroxide in 100 cc. of methanol. After neutralizing with acetic acid the solution was concentrated to 30 cc. and diluted with water to obtain complete precipitation. The precipitate was collected and crystallized from ether containing a small amount of hexane, yielding 1.35 g. of allopregnan-3,B,11a,17a-triol-20-one having a melting point of 253255 C., (11); -46 (chloroform).

Example V Allopregnan-17u-ol-3J1,20-trione. Method A. A solution of 113 mg. (1.32 mol) of chromic anhydride in 5 cc. of acetic acid and 0.5 cc. of water was added drop by drop to a stirred solution of 300 mg. of allopregnan- 3B,11a,17a-triol-20-one in 20 cc. of acetic acid maintained at 15 After 5 hours standing, the mixture was poured in water and the precipitate extracted with ether. The ether solution was washed until neutral and concentrated until crystallization started. After cooling the mixture, 150 mg. of crystalline allopregnan-17a-ol-3,11, 20-trione was obtained.

Method B.550 mg. of N-bromoacetamide were added to a solution of 300 mg. of allopregnan-3B,11a,- 17a-triol-20-one in 6 cc. of pyridine. After 40 hours standing at room temperature, the solution was diluted with 70 cc. of 1% hydrochloric acid. The precipitate was collected, washed, dried and recrystallized from ethyl acetate to give 255 mg. of allopregnan 17a-ol-3,11,20-

trione identical to theone' obtained according to Method A. Example VI Allopregnan-3/S,17a-diol-11,20-dione. A solution of of 200 mg. of allopregnan-17a-ol-3,11,20-trione in 20 cc. of ethanol was shaken at room temperature and atmospheric pressure under an atmosphere of hydrogen in the presence of 2 g. of previously reduced. Raney nickel catalyst. After 1 hour the catalyst was filtered and the solution was evaporated to dryness. The residue crystallized from ether-hexane to yield 185 mg. of allopregnan- 3B,l7a-dlOll1,20-di01l6 with a melting point of 270- 272 C.

Example VII 21-bromo-allopregnane-3fl,17a,17atriol-20-one. A solution of 0.7 g. of bromine in 7 cc. of chloroform was slowly added to a stirred solution of 1.5 g. of allopregnan- 3fi,11a,17o-triOl-20-OI1C in 15 cc. of chloroform (no hydrobromic acid was added). After adding all the bromine, the solution was diluted with chloroform and well ashed with water, dried over sodium sulphate and concentrated in vacuum at a temperature below 40. The residue crystallized from chloroform-ether to give 1.6 g. of 21-bromo-allopregnane-3 8,11a,17a-triol-20-one.

Example VIII Allopregnane- 3 5,1 1a,17a,21-tetrol-20-one 21-monoacetatc. Without further purification, the bromo compound obtained according to Example VII was dissolved in 40 cc. of acetone and mixed with a solution of 1 g. of sodium iodide in 10 cc. of acetone. After refluxing for 10 minutes, the solution was filtered to remove the sodium bromide which had formed. The solution was diluted with hexane to a volume of cc., mixed with a mixture of 7.5 g. of potassium bicarbonate and 4.5 cc. of acetic acid and the whole was refluxed during 10 hours. The mixture was concentrated to a volume of 20 cc., diluted with water and the precipitate formed was collected. After washing and drying, the precipitate was recrystallized from hexane-acetone, yielding 1.1 of allopregnan- 33,11a,17a,21-tetrol-20-one ZI-monoacetate.

Example IX Allopregnane-17a,21-diol-3,11,20-trione 21-acetate (dihydroallocortisone acetate). Method A. A solution of 101 mg. of chromic anhydride in 5 cc. of acetic acid and 0.5 cc. of water was added drop by drop to a mechanically stirred solution of 300 mg. of allopregnan-3 3,l1a, 17a,21-tetrol-20-one 21-acetate in 20 cc. of acetic acid, at room temperature. After standing 16 hours, the mixture was poured in water and the precipitate extracted with ether. The other solution was washed to neutrality, dried over sodium sulphate and concentrated until crystallization started. After cooling, the precipitate was collected to give 147 mg. of crystalline allopregnane-17a, 21-diol-3,11,20-trione 21'acetate, melting point 234- 237 C.

Method B.--620 mg. of N-bromoacetamide were added at room temperature to a solution of 300 mg. of allopregnane-3B,11a,17a,21-tetrol-20-one 2l-acetate in 6 cc. of pyridine. After 48 hours the mixture was diluted with 70 cc. of 1% hydrochloric acid and the precipitate was filtered, washed, dried and recrystallized from ethyl acetate to give 263 mg. of allopregnane-17a,21-diol-3,11, ZO-trione acetate, identical to the one obtained according to Method A.

The present application is a division of application Serial No. 307,722, filed September 3, 1952, now Patent No. 2,773,079, granted December 4, 1956.

We claim:

1. A process for the preparation of A. -allofurostene-3fl,11a,26-triol triacetate which comprises treating 22-isoallospirostan-3;9,1la-diol with acetic anhydride under pressure at a temperature of approximately 200 C.

6, A new compoundconsisting of A -aHofu1iostene- 313,11 092641'101 triacetate.

7. A new 7 compound consisting of A -allopregnene- 3 3,,11h-dio1-20-one diacet-ate.

8.. Anew compound consisting of allopregnane mmlladio1'- 20-one diacetate.

References Cited in the file'of this patent UNITED STATES PATENTS Marker July 4, 1944 Hershberg Oct. 20, 1953 OTHER REFERENCES I.A.C.S., vol. 68, pages 2478-83 (1946), byS1re:tt. Chamberlin: J.A.C.S. 73 (71951), 4052-4053. Rosenkranz: J.A.C.S. 73 (.1951), 4055-4056. 

